NAICONS Srl , Viale Ortles 22/4 , 20139 Milano , Italy.
KtedoGen Srl , Viale Ortles 22/4 , 20139 Milano , Italy.
J Nat Prod. 2019 Jan 25;82(1):35-44. doi: 10.1021/acs.jnatprod.8b00354. Epub 2019 Jan 7.
The increasing incidence of infections caused by drug-resistant pathogens requires new efforts for the discovery of novel antibiotics. By screening microbial extracts in an assay aimed at identifying compounds interfering with cell wall biosynthesis, based on differential activity against a Staphylococcus aureus strain and its isogenic l-form, the potent enduracyclinones (1, 2), containing the uncommon amino acid enduracididine linked to a six-ring aromatic skeleton, were discovered from different Nonomuraea strains. The structures of 1 and 2 were established through a combination of derivatizations, oxidative cleavages, and NMR analyses of natural and C-N-labeled compounds. Analysis of the biosynthetic cluster provides the combination of genes for the synthesis of enduracididine and type II polyketide synthases. Enduracyclinones are active against Gram-positive pathogens (especially Staphylococcus spp.), including multi-drug-resistant strains, with minimal inhibitory concentrations in the range of 0.0005 to 4 μg mL and with limited toxicity toward eukaryotic cells. The combined results from assays and macromolecular syntheses suggest a possible dual mechanism of action in which both peptidoglycan and DNA syntheses are inhibited by these molecules.
耐药病原体感染的发病率不断上升，这就需要我们努力去发现新的抗生素。通过对微生物提取物进行筛选，以鉴定能干扰细胞壁生物合成的化合物，该筛选实验基于对金黄色葡萄球菌及其同基因无壁形式的差异活性，从不同的野野村氏菌中发现了具有强大活性的环脂肽（1、2），它们含有与六元芳香骨架相连的罕见氨基酸——厄达青霉胺。通过对天然和 C-N 标记化合物的衍生化、氧化裂解和 NMR 分析的结合，确定了 1 和 2 的结构。生物合成簇的分析提供了用于合成厄达青霉胺和 II 型聚酮合酶的基因组合。环脂肽对革兰氏阳性病原体（尤其是葡萄球菌属）具有活性，包括对多种耐药菌株，其最小抑菌浓度范围为 0.0005 至 4 μg mL，对真核细胞的毒性有限。基于实验和大分子合成的综合结果，这些分子可能具有双重作用机制，既能抑制肽聚糖合成，又能抑制 DNA 合成。
